The dramatic clinical response of psoriasis to cyclosporin A has rekindled interest in the role of the immune system in psoriasis, a skin disease which affects 1-2% of the American population. The principal objective of this proposal is to take a fresh look at the role of the immune system in the etiopathogenesis of psoriasis at the molecular biochemical level by studying specific interactions between peripheral blood mononuclear leukocytes (PBML) and keratinocytes (KCs) both in vitro and in vivo with particular emphasis on gamma interferon (IFN-gamma). Focus on IFN- gamma is justified because it influences KC growth and differentiation, both of which are altered in psoriasis and because of our ability to measure functional, high affinity receptors for IFN-gamma on normal KCs by ligand binding studies which will facilitate detection of any KC IFN-gamma membrane receptor abnormalities in psoriasis. Since IFN gamma inhibits the proliferation of normal KCs and induces HLA-DR expression to 10-11M, our hypothesis is: In psoriasis, the epidermal hyperplasia and lack of KC HLA-DR expression is a reflection of either inadequate tissue levels of IFN-gamma or an altered KC response to IFN-gamma because of abnormal KC IFN-gamma membrane receptors, which leads to perpetuation of the immunobiological alterations characteristic of psoriasis. Direct PBML/KC cellular interactions which may be important in the early initiating phases of psoriasis will be studied using a simple in vitro adherence assay to investigate the molecular mechanisms of recognition and binding involved between PBML and KC. We propose to integrate immunological, biochemical and cell surface (receptor and adherence molecule) perspectives in psoriasis by dissecting specific PBML/KC interactions and by focusing on early cellular reactions which may occur in the initiation of a psoriatic lesion and the soluble mediators produced following the onset of the inflammatory process. Our simplified working model for psoriasis is similar to that proposed by Fry et al (Imm Tod 7:256, 1986): 1) Psoriasis is triggered by the appearance of a putative psoriasis antigen (related to streptococcal or viral antigen, drugs, trauma, etc.) with initiation of tissue injury. 2) There is early macrophage-T cell interaction to "antigen" with PBML activation and production of lymphokines (IL-1, IL-2, etc. - which may be inhibited by cyclosporin A). 3) There is infiltration into epidermis with adherence of PBML to KCs with perpetuation of "microwounding" and further release of lymphokines, some of which may stimulate KC repair (i.e., IL-1) and others which inhibit KC proliferation (i.e. IFN-gamma). 4) The reparative KC hyperplasia "overshoots" and hyperproliferation dominates because of either a) low IFN- gamma levels or b) altered KC IFN-gamma receptors (either intrinsic or acquired from neutrophil/mast cell proteinases, for example). This scenario would be consistent with the Koebner reaction, the clinical responsiveness to cyclosporin A and the immunohistological features of psoriasis. Our results should not only yield valuable information with respect to psoriasis, but also aid in our understanding and treatment of many other inflammatory skin diseases.